Antipsychotics and the Shrinking Brain

In the February 2011 issue of the Archives of General Psychiatry, Ho and colleagues1 published an article that examined the relationship between long-term antipsychotic treatment and brain volume in first-episode schizophrenia patients. That paper triggered considerable media attention. Because it was widely interpreted as showing that antipsychotics damage the brain, it may have caused many people—both patients and family members—to reconsider whether to take their prescribed medication.

As is so often the case, the picture is far from clear.

Ho and colleagues performed structural brain imaging every 3 years for up to 14 years in 211 first-episode patients who had been treated naturalistically. In the beginning, 15% were medication-naive and the majority were treated with first-generation antipsychotics; by the third scan, this had changed to most receiving second-generation antipsychotics and 23% receiving clozapine. On average, each subject was scanned 3 times and had already been treated for 5 months before the first scan.

The investigators found that gray matter volumes of all brain regions except for the cerebellum decreased over time; white matter volume on average was unchanged. Subjects who had received higher average lifetime doses of an antipsychotic had less gray matter at baseline and at all future time points. Neither antipsychotic dose nor type of antipsychotic (first-generation, second-generation, or clozapine) appeared to influence the rate at which gray matter loss progressed over time. In contrast, patients who received a low-dose antipsychotic tended to have modest increases in white matter volume over time compared with modest white matter loss in patients whose lifetime average dose was higher. The only advantage for second-generation antipsychotics over typical antipsychotics was a reduction in parietal white matter loss over time.

If we were to draw conclusions from this study alone, it would appear that gray matter loss can’t be altered by reducing antipsychotic exposure or by switching antipsychotic class—it just happens. The one possible benefit of a low-dose antipsychotic, the preservation of white matter, is of unclear clinical significance, as is the possible increase in parietal white matter with second-generation agents. However, the story gets more complicated as we look earlier in the course of treatment.

Back in 2007, Ho and colleagues2 published a report based on roughly half their current sample. In this analysis, they discovered that antipsychotic dose was related to the rate of loss of frontal gray matter, but only in medication-naive patients. Frontal gray matter loss, in turn, corresponded with cognitive decline. These relationships disappeared if subjects had been treated with medication before baseline scanning—in these subjects, brain-derived neurotrophic factor (BDNF) genotype predicted the rate of gray matter loss and the pattern of cognitive deficits. This suggests that gray matter loss associated with antipsychotic dose may have been missed entirely in the recent publication by Ho and colleagues because it may occur very early in treatment—before the baseline scan in the great majority of subjects.

Many additional potential confounds complicate these findings. First, it’s not possible to determine whether higher antipsychotic doses are contributing to the progression of brain loss or are merely a response to it. In the absence of an untreated control group, it’s also not possible to detect neurotoxic effects of drugs that are not related to dose and, without a healthy control group, it is not clear which changes in brain volume are pathological.

Animal studies can begin to address these issues. A study in monkeys conducted by David Lewis’ group prompted concern about antipsychotic neurotoxicity several years ago. Monkeys treated with haloperidol and olanzapine for 17 to 27 months lost roughly 10% of their total brain volume, both gray and white matter, compared with sham-treated controls, with greatest volume loss in frontal and parietal cortex.3 Further examination revealed a reduction in the number of glial cells4; a similar postmortem finding in schizophrenia brains previously had been attributed to the illness. However, this study included only 6 monkeys per treatment group and did not provide information on the time course of neurotoxic changes.

Other studies suggest that antipsychotic effects on brain volume may occur rapidly. For example, Vernon and colleagues5 found a significant loss of frontal cortical volume after only 8 weeks in rats given haloperidol or olanzapine.

Evidence of the rapidity at which antipsychotics can affect brain volume in humans was recently provided by Tost and associates.6 These investigators found a significant, reversible decrease in striatal volume in healthy subjects within 2 hours after they were treated intravenously with haloperidol. Loss of striatal volume powerfully predicted neurological adverse effects.

Taken together, these studies suggest that antipsychotics may contribute to early gray matter loss and, later in the course of treatment, to white matter loss. These effects may be dose-related and probably are not prevented by the use of second-generation agents. This argues for minimizing antipsychotic exposure both acutely and long-term. However, we are left with the additional dilemma that a longer duration of untreated psychosis (DUP) may also be neurotoxic. Longer DUP has been associated with poorer symptomatic and functional outcomes7 as well as brain volume loss.8 Studies of DUP have their own methodological limitations and controversies, but they should serve to warn us that the rapid control of psychosis may also be important.

Psychosis at any phase of the illness can be extremely distressing, disruptive, and potentially dangerous for patient and family. New approaches for early intervention are needed and, with existing drugs, the potential for neurotoxicity must be weighed against short-term and long-term clinical gains. In the meantime, clinicians should avoid using antipsychotics unnecessarily and, when needed, use the lowest effective dose.